For archival purposes, below find my webcast and conference call notes for various events in 2010-2011.

For archival purposes, below find my webcast and conference call notes for various events in 2010-2011.

11/30/2010 webcast

2 of the 4 Mipo phase 3 trials are for the first indication- homozygous FH and severe heterozygous FH/severe high cholesterol

Benchmark for Mipo pricing is apheresis, which is about $100k per year in the US, slightly lower in EU

BMS-PCSK9 drug also lowers LDL levels, but by different mechanism than mipomersin

PTP1b inhibitor- two short term studies of this insulin sensitizer complete so far. Good activity in multiple endpoints but not H1bAc (but changes in this often not seen until 6 month duration studies- slow effects). Goal is long term studies (6-12 months next). In parallel with long term tox of this drug, also moving forward a more potent backup compound. Also see LDL lowering with this drug- not enough as a stand-alone, but a nice complement for treating diabetes

SGLT2 phase 2 trials in 2011

GCCR and GCGR in preclinical tox now, phase 1 trials in 2011

eIF-4E start p2 trials in 2010 in prostate cancer and NSCLC. $LLY has the right to take these drugs back after positive phase 2 data at dramatically better terms. ISIS had re-taken over the compounds to accelerate their development

Success of any one drug in the pipeline moves the company to be sustainably cash flow positive

Since ISIS has much more cash on hand now vs a few year ago, they can keep drug longer, through phase 2 to capture more of the value

12/7/2010 Webcast

CRP p2 trials to start late 2010 or in 2011

FXI p1 trial to begin early 2011

PTP1b "getting ready" for p2b trials

Survivin inhibitor "about ready" for phase 3

eIF4E inhibitor p2 trials to start any day now

2011, will add 3-5 more drugs to pipeline and transition to gen 2.5 chemistry

1/6/2011 Pipeline Update webcast

Next week there will be an update with info from pre-NDA meeting Genzyme had with FDA re mipomersen

No other Stat3 drugs in development. Top cancer targets are lung, liver, myeloma

Current obesity drugs- attempt to suppress appetite in CNS, ISIS goal is drugs that act peripherally to increase metabolism

Have evaluated scores of obesity targets before selecting FGFR4 as first one- toxicology and PK studies underway to allow IND for this 1h2011

Gen 2.2 chemistry is basically same as 2.0, but use knowledge to improve potency

No plans to convert current pipeline to Gen 2.5 chemistry

Will introduce Gen 2.5 cautiously, first in cancer and serious diseases- will select first candidate in 2011 and several more in 2012, follow later with chronic disease drugs

Events coming up in near future (by the time of spring 2011 conference call to discuss pipeline

Initiate phase 1 for Factor XI drug

Update on CRP drug, initiate phase 2 in multiple myeloma

Move SGLT2 drug towards phase 2

Some insight into timing of PTP1b inhibitor phase 2b trial "as we round the bend in long-term toxicology studies"

Excalliard EXC001 phase 2 data so far are "thrillingly positive", rest will be released soon

ISIS has sufficient manufacturing capacity to launch mipomersen and to supply the entire pipeline for teh foreseeable future- they expanded the facility in 2010

4q2010 conference call will include a comprehensive list of events/milestones for 2011

ISIS does not anticipate new discovery partnerships, but looking at more option deals like done with GSK

Do not expect any data on oral delivery in 2011- ISIS is working on formulations now that have the selected chemistry

The recent meeting was the first time $GENZ discussed the severe heterozygous familial hypercholesterolemia (HeFH) population with the FDA. In the US, will need a separate filing for this indication

The severe HeFH indication will not require an outcome study, but will require an additional study with 12 month exposure to the drug (previous studies were 6 month only, some pts were on for >1 yr, but FDA wants larger database

The required trial is "within the scope of the planned development program" and will be of "reasonable size" [not disclosed specifics], currently preparing the clinical trial design

FDA is pleased with quality of current 12 month safety database (107 total pts), is more than enough info for homozygouse FH population, just wants more data for severe HeFH- still only need to look at lowering of LDL cholesterol endpoint

Analyst question referred to ICH guideline re trial size, ISIS mgmt indicated this was in the right range (anyone know what this is?)

HoFH US NDA filing may be delayed to 2nd half 2011 because now is different vs European filing (hoFH and severe HeFH are treated as a single continuum and can combine the filings in EU)

HoFH indication would include up to about 3000 pts in US- this depends on the precise definition for labeling as negotiated with FDA

HeFH represents 1 in 500 of the US population (~600,000)

ISIS will finish their funding commitment for the GENZ partnership sometime in 2011, costs are split equally after that

$GENZ submission of Mipomersen NDA will trigger $25m milestone payment (EU filing will be 1h11, US may shift to 2h)

2011 expect operating expenses to increase ~$15m over 2010 ($5m associated with moving to new R&D building in mid-2011)

Later in 2011 will start sharing Mipo expenses equally with GENZ/SNY

2011 Guidance: net loss of low $40m's and year end cash balance greater than $350m (is conservative but includes above mipo milestone)

HoFH- 300 pts in US by genetics, 3000 by clinical definition

"I'll compare all Phase 3 program to that of the MTP inhibitor. The MTP inhibitor being developed by Integreon has reported a single uncontrolled study with 29 patients individually dose titrated to maximally tolerated dose, while on a very restricted diet to avoid exasperating diarrhea caused by the drug. Clearly the overall profile of Mipomersen demonstrates that Mipomersen is a cut above the competition including anything on the horizon and of course we have completed a much more thorough Phase 3 program than the MTP inhibitor."

Detailed data from final 2 phase 3 mipo trials will be presented at ACC April 2011

SGLT2 data 2011

$25m additional milestone for US approval. No milestones for EU submission/approval

Statins reduce CRP by 15-30%, hope that can get much more than that w/ antisense in p2

"We set up Regulus to be successful and what that would mean eventually is that it would become a public company"...no comment on when/how to monetize stake

Unless we hear otherwise, EU mipo filing will include severe HeFH

CRP program: "So initially, and for this year, we are planning to move into two Phase 2 programs, one in rheumatoid arthritis in which the endpoints will be of course CRP but also symptomology in the disease and the second is in multiple myeloma for which we will be looking at not only the reduction of CRP but also symptomology and chemosensitization. "

Initial US filing based on 733 pts, inc 107 for > 1 yr, would expect label to require similar liver monitoring as statins

3/1/2011 Citi webcast

Gray fuzzy line exists between HoFH and severe HeFH

HoFH- 700 different mutations identified in LDL receptor

HoFH- in US and EU, this condition is not diagnosed by genetic testing, but instead clinically/phenotypically based on exceedingly high LDL >300 while on maximally tolerated statins

Severe HeFH- present clinically with very high LDL, in US are eligible for apheresis (but fewer than 30 centers exist in nation). Market of 10,000-16,000 pts in US. EU sees a continuum of disease, does not segregate HoFH and severe HeFH

GENZ is in conversations to define the protocol for a 1 year controlled severe HeFH safety and efficacy trial (only 9 severe HeFH pts are among those that have been on therapy over 1 yr)

Over 100 pts have been on mipo over 1 yr, over 50 pts are still on the extension study being managed by Genzyme

Observations of liver fat deposits and liver enzyme elevations are related to the target of mipo, not antisense in general

In Europe, their advice and feedback suggests they look at the population differently vs FDA. Much of the discussion is related to the 2nd filing to expand mipomersen to all HeFH patients

Mipomersen is contained within the rare diseases unit of Genzyme that SNY has said would not be changed- so don't think SNY would return rights to drug

Competing candidate (Adurion sp?)- NDA filed this year with only 29 pts, mipomersen has much larger population

3/16/2011 Barclays webcast

Mipomersen- seen moderate increases in liver fat deposits, doing further work now to assess the clinical significance

Injection site reactions are largely consmetic, but working on new mipo dosing regimens to alleviate this

Finalizing design of 12 month mipo study needed for severe HeFH population NDA filing in US

about 5% equity ownership in Excalliard, milestones typical of early partnering deals

PTP1b (Sanjay)

late 2009 positive p2 study

efforts on this program over last yr "invisble to those outside ISIS"

diabetes is 7th leading US cause of death. 60% of pts poorly controlled. half of type 2 pts progress and need insulin (goal to extend the time before this is necessary)

insulin sensitizer- can help body's own or exogenous insulin

small molecule PTP1b inhibitors have off target effects on closely related proteins

ptp1b inhib also reduces LDL- seen in p2 studies

many advantages over PPARs

2 p2 trials completed w/ 715 give POC and safety

next step: longterm clinical studies

in the process of preclinical studies needed, discovered new more potent drug. 5x inc potency should result in better clinical activity- will move this drug forward instead- IND-enabling studies done. complete p1 and move into p2 studies 2012 combo with insulin and metformin. accel path based on 715 experience. significantly longer patent life (this announcement has been a long time coming and was clear as day- they have weasel worded around this program for over a year before officially admitting this today- finally switched the pipeline to show as preclinical instead of phase2 asset)

GSK1 now disclosed and will be known as TTRrx

inhibit transthyretin (TTR) for TTR amyloidosis

no current tx, incidence 1 in 100,000, so 50k pts worldwide

mutant form of protein- accumulates slowly in tissues, impairing function

any one opportunity in which lowering CRP helps clinically could be $1b mkt

"ready to begin these p2 studies" finish first two trials 2012 and expand to additional indications then

1q earnings in 2 weeks.

Q&A

Needham

each satellite deal is slightly different. but typically some equity, license fee, milestones (similar to early discovery partnership because usually ISIS has not done any work yet when partnered). royalties typically 5-10%

exception-30% owenerhship in OGXI drug.

TTR- FoldRx and Amicus related competing pgms.-these attempt to stabilize mutant fibriles and make clusters soluble. best can hope for is some fraction of protein is prevented from forming these

Normal form of TTR protein also participates in the disease

TTR excreted from lvier to blood- could measure reductions of this early on in p1

Morgan Joseph

715 not going to continue developing. may seek to license (this statement was very half-hearted...not going to happen). one of earliest generation 2.0 compounds

backup more potent and longer halflife. expect to move much faster due to experience, didnt have the funding early to do the 26wk studies knew were necessary (this is annoying for an investor to hear). move quickly thru p1 then directly into 6 month studies in diabetics. long term toxicology studies will be in place in 2012